Background Oligoteratoasthenozoospermia (OTA) combines deteriorated quantity, morphology and motility of the sperm, resulting in male factor infertility.
Methods We used whole genome genotyping and exome sequencing to identify the mutation causing OTA in four men in a consanguineous Bedouin family. We expressed the normal and mutated proteins tagged with c-Myc at the carboxy termini by transfection with pCDNA3.1 plasmid constructs to evaluate the effects on protein stability in HEK293 cells and on the kinetics of actin repolymerisation in retinal pigment epithelium cells. Patients’ sperm samples were visualised by transmission electron microscopy to determine axoneme structures and were stained with fluorescent phalloidin to visualise the fibrillar (F)-actin.
Results A homozygous missense mutation in Ciliogenesis Associated TTC17 Interacting Protein (CATIP): c. T103A, p. Phe35Ile, a gene encoding a protein important in actin organisation and ciliogenesis, was identified as the causative mutation with a LOD score of 3.25. The mutation reduces the protein stability compared with the normal protein. Furthermore, overexpression of the normal protein, but not the mutated protein, inhibits repolymerisation of actin after disruption with cytochalasin D. A high percentage of spermatozoa axonemes from patients have abnormalities, as well as disturbances in the distribution of F-actin.
Conclusion This is the first report of a recessive mutation in CATIP in humans. The identified mutation may contribute to asthenozoospermia by its involvement in actin polymerisation and on the actin cytoskeleton. A mouse knockout homozygote for CATIP was reported to demonstrate male infertility as the sole phenotype.
- molecular genetics
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Contributors MA performed the genetic studies and all experiments. AH, El Lev and Ei Lun contributed the clinical data. AH recruited the patients. IH-V and TP supervised and performed the sperm analyses, respectively. MG contributed the tests of CATIP variations in additional infertility patients, fertile men and 500 control individuals from the Israeli population. CS contributed to the linkage analyses. VS contributed to the design of the genetic study and experiments. RP designed and supervised all the studies and prepared the manuscript. MA, AH, Ei Lun and VCS contributed to the preparation and revision of the manuscript.
Funding This study was funded by The Fertility Hub, Faculty of Health Sciences Ben-Gurion University of the Negev, and The Israeli Ministry of Science, Technology and Space.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the Soroka Medical Center institutional review board, and all participants have signed a written informed consent when recruited.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.